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ORIGINAL ARTICLE

A systematic review of salivary gland hypofunctionand xerostomia induced by cancer therapies: prevalence,severity and impact on quality of life

S. B. Jensen & A. M. L. Pedersen & A. Vissink &

E. Andersen & C. G. Brown & A. N. Davies & J. Dutilh &

J. S. Fulton & L. Jankovic & N. N. F. Lopes &

A. L. S. Mello & L. V. Muniz & C. A. Murdoch-Kinch &

R. G. Nair & J. J. Napeñas & A. Nogueira-Rodrigues &

D. Saunders & B. Stirling & I. von Bültzingslöwen &

D. S. Weikel & L. S. Elting & F. K. L. Spijkervet &M. T. Brennan &

Salivary Gland Hypofunction/Xerostomia Section,Oral Care Study Group, Multinational Associationof Supportive Care in Cancer (MASCC)/InternationalSociety of Oral Oncology (ISOO)

Received: 11 November 2009 /Accepted: 26 January 2010 /Published online: 17 March 2010# Springer-Verlag 2010

AbstractPurpose This systematic review aimed to assess the literaturefor prevalence, severity, and impact on quality of life ofsalivary gland hypofunction and xerostomia induced bycancer therapies.

Methods The electronic databases ofMEDLINE/PubMed andEMBASEwere searched for articles published in English sincethe 1989 NIH Development Consensus Conference on theOral Complications of Cancer Therapies until 2008 inclusive.Two independent reviewers extracted information regarding

S. B. Jensen (*) :A. M. L. PedersenDepartment of Oral Medicine, Clinical Oral Physiology,Oral Pathology & Anatomy, Institute of Odontology,Faculty of Health Sciences, University of Copenhagen,Nørre Allé 20,2200 Copenhagen, Denmarke-mail: [email protected]

A. M. L. Pedersene-mail: [email protected]

A. Vissink : F. K. L. SpijkervetDepartment of Oral & Maxillofacial Surgery,University Medical Center Groningen, University of Groningen,P.O. Box 30.001, 9700 RB Groningen, The Netherlands

A. Vissinke-mail: [email protected]

F. K. L. Spijkervete-mail: [email protected]

E. AndersenDepartment of Oncology, Herlev University Hospital, Herlev Ringvej,2730 Herlev, Denmarke-mail: [email protected]

C. G. BrownSchool of Nursing, College of Health Sciences,University of Delaware, Newark, DE 19716, USAe-mail: [email protected]

A. N. DaviesDepartment of Palliative Medicine, Royal Marsden Hospital,Sutton SM2 5P5, UKe-mail: [email protected]

J. DutilhDutilh Instituto de Reabilitação Facial e Oral,R. Paula Bueno 307,Taquaral, Brazile-mail: [email protected]

J. S. FultonDepartment of Adult Health,Indiana University School of Nursing, 1111 Middle Drive,Indianapolis, IN 46202, USAe-mail: [email protected]

Support Care Cancer (2010) 18:1039–1060DOI 10.1007/s00520-010-0827-8

study design, study population, interventions, outcome meas-ures, results and conclusions for each article.Results The inclusion criteria were met by 184 articlescovering salivary gland hypofunction and xerostomiainduced by conventional, 3D conformal radiotherapy orintensity-modulated radiotherapy in head and neck cancerpatients, cancer chemotherapy, total body irradiation/hema-topoietic stem cell transplantation, radioactive iodinetreatment, and immunotherapy.Conclusions Salivary gland hypofunction and xerostomiaare induced by radiotherapy in the head and neck regiondepending on the cumulative radiation dose to the glandtissue. Treatment focus should be on optimized/newapproaches to further reduce the dose to the parotids, andparticularly submandibular and minor salivary glands, asthese glands are major contributors to moistening of oral

tissues. Other cancer treatments also induce salivary glandhypofunction, although to a lesser severity, and in the caseof chemotherapy and immunotherapy, the adverse effect istemporary. Fields of sparse literature included pediatriccancer populations, cancer chemotherapy, radioactive iodinetreatment, total body irradiation/hematopoietic stem celltransplantation, and immunotherapy.

Keywords Cancer therapy . Radiotherapy . Chemotherapy .

Salivary gland hypofunction . Xerostomia . Quality of life

Introduction

Saliva plays a crucial role in the maintenance of toothintegrity, dilution of food detritus and bacteria, and by

L. JankovicClinic for Periodontology and Oral Medicine,Faculty of Stomatology, University of Belgrade, P.O. Box 506,11000 Belgrade, Serbiae-mail: [email protected]

N. N. F. LopesPediatric Dentistry, Service of Oral Medicine,IOP-Pediatric Oncology Institute/GRAACC,Federal University of São Paulo, Rua Botucatu 743,CEP 04023-062 São Paulo, Brazile-mail: [email protected]

A. L. S. MelloDepartment of Endocrinology, Federal University of São Paulo,Medicine Paulista School, Rua Pedro de Toledo 910,São Paulo, Brazile-mail: [email protected]

L. V. MunizDepartment of Odontology,Associação do Combate ao Câncer do Centro Oeste de Minas Gerais,Instituto de Pesquisas Oncológicas Minas Gerais, IPOM,Hospital do Câncer Centro Oeste de Minas Gerais,Minas Gerais, Brazile-mail: [email protected]

C. A. Murdoch-KinchDepartment of Oral and Maxillofacial Surgery/Hospital Dentistry,School of Dentistry, University of Michigan,1011 North University Ave,Ann Arbor, MI 48109-1078, USAe-mail: [email protected]

R. G. NairCentre for Medicine and Oral Health, Griffith University,Gold Coast Campus, QLD 4222 Gold Coast, Australiae-mail: [email protected]

J. J. Napeñas :B. Stirling :M. T. BrennanDepartment of Oral Medicine, Carolinas Medical Center, P.O.Box 32861, Charlotte, NC 28232, USA

J. J. Napeñase-mail: [email protected]

B. Stirlinge-mail: [email protected]

M. T. Brennane-mail: [email protected]

A. Nogueira-RodriguesDepartment of Oncology and Research,Associação do Combate ao Câncer do Centro Oeste de Minas Gerais,Instituto de Pesquisas Oncológicas Minas Gerais, IPOM,Hospital do Câncer Centro Oeste de Minas Gerais, Minas Gerais,Brazile-mail: [email protected]

D. SaundersDepartment of Dentistry,Sudbury Regional Hospital Cancer Program,Hôpital régional de Sudbury Regional Hospital,41 Ramsey Lake Road,Sudbury, ON P3E 5J1, Canadae-mail: [email protected]

I. von BültzingslöwenDepartments of Oral Immunology and Oral Medicine, Instituteof Odontology, Sahlgrenska Academy, University of Gothenburg,Medicinaregaten 12,413 90 Gothenburg, Swedene-mail: [email protected]

D. S. WeikelDepartment of Pathology and Diagnostic Sciences,University of Maryland Dental School and GreenebaumCancer Center, Baltimore, MD 21201, USAe-mail: [email protected]

L. S. EltingDepartment of Biostatistics,The University of Texas M.D. Anderson Cancer Center,1515 Holcombe Blvd,Houston, TX 77030, USAe-mail: [email protected]

1040 Support Care Cancer (2010) 18:1039–1060

mechanical cleansing of the oral cavity. Saliva alsoprovides antimicrobial activity preventing oral infectionsand plays an important part in the upper gastrointestinalfunctions including taste perception, formation of foodbolus, facilitation of mastication, swallowing and speech, aswell as lubrication of oropharyngeal and upper esophagealmucosa (for review, see Pedersen et al. [1]). Whole saliva isthe designation for the mixed fluid in the mouth, whichderives from the major salivary glands (the parotid,submandibular, and sublingual glands, which account for90% of the saliva production) and the minor salivary glands(which account for the remaining 10%). Under restingconditions, about two-thirds of the saliva is produced by thesubmandibular glands, which comprise both serous andmucous acinar cells and produce a viscous mucin-rich fluid,while the sublingual glands contribute with 1–2% andmainly consist of mucous acinar cells [2]. The serousparotid glands produce a watery and protein-rich fluid that,upon stimulation, accounts for about 50% of the totalvolume of saliva [3]. Even though the minor salivary glandsproduce only 10% of the total volume of saliva, they play asignificant role in lubricating the mucosa [4]. The sensation oforal dryness may occur when a person’s normal unstimulatedflow rate is reduced by about 45–50% [5, 6]. Hyposalivation,a pathologic low saliva secretion, is commonly defined as aresting whole saliva flow rate of ≤0.1 ml/min and/or astimulated whole saliva flow rate of ≤0.5 ml/min [7].

Salivary gland hypofunction, usually accompanied by apersistent feeling of a dry mouth, implies a seriouslyincreased risk of development of oral infections andcarious destruction of teeth, oral mucosal discomfort andpain, hampered oral functioning, and a worsened nutri-tional state. As a consequence, patients with salivary glandhypofunction usually are restricted in their daily activities,have a poorer general well being, and are handicapped intheir social interactions [8]. Regarding head and neckcancer treatment, it is well accepted that salivary glandhypofunction (objective evidence of reduced salivaryoutput) and xerostomia (subjective feeling of dry mouth)are significant morbidities during and following radiother-apy involving exposure of the major and minor salivaryglands [9]. The salivary glands are superficially locatedcompared to most head and neck tumors, and thus, theionizing radiation has to pass through the salivary glands toeffectively treat the tumor. In contrast, no firm conclusionhas been reached in the literature regarding whetherchemotherapy induces salivary gland hypofunction/xerosto-mia [10], and studies on this subject as well as other cancertreatments such as radioactive iodine treatment and totalbody irradiation/hematopoietic stem cell transplantation aresparse in comparison to the substantial number of publica-tions on salivary gland sequelae induced by irradiation of thehead and neck.

In 1989, a NIH Development Consensus Conference onOral Complications of Cancer Therapies was held [11].General consensus from this conference that applied tosalivary gland hypofunction and xerostomia could be sum-marized as follows: (1) to establish baseline data with whichall subsequent examinations can be compared and (2) toidentify risk factors for the development of oral complications.These recommendations resulted in some directions for futureresearch applicable to salivary gland hypofunction andxerostomia, viz., (1) to devise accurate, quantifiable, repro-ducible criteria for assessing and classifying oral complica-tions of cancer therapy, (2) to determine incidence andprevalence of oral complications related to different types ofanticancer therapies and related risk factors, and (3) to studythe mechanisms of cancer treatment injury to the hard and softoral tissues at the molecular and cellular level and determinehow these affect the oral environment.

This systematic review represents a search and evalua-tion of the literature appearing since the 1989 NIHDevelopment Consensus Conference on the Oral Compli-cations of Cancer Therapies [11] and the related publicationof the National Cancer Institute (NCI) monographs 1990[12] in order to clarify the impact of newer cancer therapieson the prevalence and severity of salivary gland hypofunc-tion and xerostomia. The aims of the current review were(1) to assess the prevalence and severity of salivary glandhypofunction and xerostomia by cancer therapy regimenand (2) to assess the impact of salivary gland hypofunctionand xerostomia on quality of life (QoL).

Systematic review methodology

Search strategy and criteria for selecting studies

A systematic literature search was conducted with assis-tance from a research librarian in the databases MEDLINE/PubMed and EMBASE for articles published between 1January 1990 and 31 December 2008. The primaryoutcome was to trace all literature containing original dataon prevalence of salivary gland hypofunction and/orxerostomia as well as the economic burden, impact on oralhealth-related QoL, or management strategies of salivarygland hypofunction and xerostomia in cancer patientsundergoing head and neck radiotherapy, chemotherapy, orcombined treatment modalities.

The literature search including 31 December 2007 wasperformed in March 2008 and an update including 31December 2008 was performed in April 2009 usingcombinations of the MeSH terms of [Saliva] OR [SalivaryGlands] OR [Salivation] OR [Salivary Gland Diseases] OR[Xerostomia] AND [Neoplasms] OR [Head and NeckNeoplasms/Radiotherapy] OR [Radiotherapy] OR [Anti-

Support Care Cancer (2010) 18:1039–1060 1041

neoplastic Agents] OR [Antineoplastic Combined Chemo-therapy Protocols] OR [Combined Modality Therapy] OR[Total Body Irradiation] OR [Bone Marrow Transplanta-tion] OR [Hematopoietic Stem Cell Transplantation] AND[Humans] AND [1990/01/01:2008/12/31]. In MEDLINE/PubMed, the MeSH term [Xerostomia] is presently definedas “decreased salivary flow” and not as the subjectivefeeling of having a dry mouth (decreased salivary flowshould be hyposalivation or salivary gland hypofunction);therefore, the search was exploded to include the text wordsof [dry mouth] and [oral dryness]. The search results wereimported into a computerized database (Reference ManagerVersion 12). The search results from each of the electronicdatabases of MEDLINE/PubMed and EMBASE werecombined, and duplicate publications were eliminated.

The following publication types were eliminated fromthe present systematic review: systematic and non-systematic reviews; studies not reporting actual data onxerostomia/salivary gland hypofunction; studies reportingdata from previous publications or with a relevant laterfollow-up publication; phase I and II studies, opinionpapers, and case reports; articles published before 1990;and articles from the 1990 NCI monographs [12] basedon the 1989 NIH Development Consensus Conference onthe Oral Complications of Cancer Therapies [11]. Further-more, the search was limited to English language. Genderand age were not limited. Studies addressing prevalence,severity, and QoL related to different types of anticancertherapies are reported in the present paper, whereasinterventional studies addressing management strategiesand the search for economic impact are reported in Jensenet al. [13].

Review method

The abstract of each article was reviewed by the salivarygland hypofunction/xerostomia section head (SBJ) and thesystematic review organizer (MTB). Irrelevant citationswere removed according to the criteria mentioned above(publication types) creating a preliminary set of potentiallyrelevant publications. Then, the full text articles weredistributed to the reviewer team along with an evaluationform customized for reviewing salivary gland hypofunc-tion/xerostomia data [14]. This form was modified by thereview group during calibration sessions from “Form T.Evaluation of studies assessing the effects of intervention”[15]. Each reviewer then independently evaluated a numberof allocated articles. Two independent reviewers extractedinformation regarding study design, study population,interventions, outcome measures, methods, results, andconclusions for each article. The evaluation results werecompared and re-evaluated until consensus was reachedbetween two reviewers.

The review team was recruited from the Oral CareStudy Group (chair, FKLS), Multinational Association ofSupportive Care in Cancer (MASCC)/International Societyof Oral Oncology (ISOO) and calibrated at teleconferences,by email correspondences and/or at the Salivary GlandHypofunction/Xerostomia Group Meeting at the MASCC/ISOO Symposium, Houston, TX, June 2008. The reviewersincluded experts in the areas of salivary gland hypofunctionand xerostomia and included the following disciplines: oralmedicine, oral pathology, clinical oral physiology, oraloncology, oncology nursing, radiation oncology, oral immu-nology, pediatric dentistry, oral and maxillofacial surgery,palliative oncology, periodontology, epidemiology, andbiostatistics.

Statistical estimation of salivary flow rate and prevalence/severity of xerostomia

Results of salivary flow rates and prevalence and severity ofxerostomia were extracted when available from the includedstudies. The data were weighted and pooled. Qualityweighting of the data included in the estimation of salivaflow rate and prevalence and severity of xerostomia wasbased on sources of bias, representativeness, scale validity,and sample size. Further details of the quality weighting anddata handling have been reported elsewhere [14].

Results

Description of studies

The electronic searches identified over a thousand titles andabstracts and from which a total of 356 potentially relevantpublications were selected according to the defined criteria.After examination of the abstracts and full-text articles by thereview group, 101 articles were excluded for reasonssummarized in Table 1, and 255 articles satisfied the inclusioncriteria. Regarding cancer treatment, number of studies, andstudy designs of the included studies, see Table 2.

Of the 255 trials included, 238 (93%) assessed adultpopulations, six (2%) assessed mixed adult and pediatricpopulations, and 11 (4%) included populations of childrenand adolescents.

Methodological issues of included studies

Regarding evaluation of salivary gland function, discrepanciesin the definitions of salivary gland hypofunction and xero-stomia were observed. Xerostomia, i.e., the subjective feelingof dry mouth, was at times being confused with and used as asynonym of salivary gland hypofunction or hyposalivation,i.e., the objective measure of decreased saliva secretion.


Between studies, considerable variation was foundregarding saliva collection procedures [whole saliva,selective parotid saliva (single or both glands pooled), orsubmandibular/sublingual saliva, all major glands pooledafter collection], stimulatory state of the glands (unstimu-lated, stimulated by chewing paraffin wax, parafilm, rubber,rubber ring, surgical latex tube, vitamin C tablets, cornchips, chewing gum, sucking on lemon candy, or oralapplication of 1%, 2%, or 5% citric acid) and flow rateunits, i.e., ml/min, ml/2 min, ml/5 min, ml/10 min, g (notime unit), g/2 min, g/5 min, g/10 min, and percent changewith/without reporting of baseline values. Furthermore,assessments were carried out at a wide range of differenttime points during and after cancer treatment and, in somecases, ranges from a few months to several years aftercancer therapy were pooled within studies.

Great diversity existed in data reporting, i.e., incidence/prevalence, mean, standard deviation, standard error of themean, median, range, 95% confidence interval, no indica-tions of variability, and reporting of actual data in tables orreporting in figures (not always readable from figures).When reporting descriptive statistics and estimates based on

salivary flow rate data, these data tend not to be normallydistributed, but may be skewed to the lower end.

Furthermore, multiple different validated or unvalidatedassessment scales of xerostomia and xerostomia-relatedQoL were used. Within studies, heterogeneity of cancerdiagnoses and cancer treatment regimens was found.

Another general characteristic was that studies lackedreporting on confounding factors known to influencesalivary gland function, e.g. co-morbidities and medicationintake (xerogenic medications and polypharmacy).

The above mentioned methodological issues madecomparing results challenging both within study groupsand between studies.

Salivary gland hypofunction and prevalenceof xerostomia by cancer therapy regimen

Radiation therapy in head and neck cancer

The systematic review of the literature of radiation therapyin head and neck cancer is presented for separate radiation

Table 2 Cancer treatments associated with salivary gland hypofunction and xerostomia

Treatment strategy Number of studies RCT Cohort Case–control Cross-sectional

Conventional RT 82a 59 1 22

3D conformal RT 14b 13 1

IMRT 49b 2 38 2 7

Mixed head and neck RT regimens 1 1

Radioactive iodine treatment 10 8 2

Conditioning TBI/CT and HSCT 11c 9c 3c

CT 16a 10 6

Immunotherapy 3 3

RCT randomized controlled trials, RT radiation therapy, 3D three-dimensional, IMRT intensity-modulated RT, TBI total body irradiation, CTchemotherapy, HSCT hematopoietic stem cell transplantationa One study included both conventional RT and CTbOne study was counted in both 3D conformal RT and IMRTcOne study included both cohort and cross-sectional design

Reason for exclusion Number of articles

Review 2

Case report 1

Phase I-II trials 41

Not sufficient data on salivary gland hypofunction or xerostomia 18

No data presented on salivary gland hypofunction or xerostomia 27

Salivary gland hypofunction/xerostomia not induced by cancer therapy 6

Data from previous publication or later follow-up publication relevant 2

Anecdotal intervention, not relevant 3

Published before 1990 1

Table 1 Reasons for exclusionidentified during reviewing(not apparent from literaturesearch)


regimens, i.e., conventional radiation therapy, 3D confor-mal radiotherapy and intensity-modulated radiation therapy(IMRT). However, regarding the extraction of data for ourestimates of prevalence and severity of xerostomia andsalivary gland hypofunction, the numbers available ongrading of xerostomia and salivary flow rates were notsufficient to split by type of radiation regimen.

Xerostomia data could be determined from 79 studiesand salivary flow rate data from 46 studies.

For all head and neck radiation regimens pooled, theweighted xerostomia prevalence and severity [by visualanalog scale (VAS) and grades 1-4), and the salivary flowchanges are presented in Table 3 and Figs. 1, 2 and 3. Theresults showed a 93% prevalence of xerostomia duringirradiation followed by slightly lower prevalences in therange of 73.6–85.3% from 1 month to more than 2 yearspost-treatment compared to 6.0% before treatment (Table 3and Fig. 1). Along this line, the severity of xerostomiameasured by VAS (1–100) showed an unchanged mediumscore from 1 month to more than 2 years post-treatment(Fig. 2). The severity grading of xerostomia (grades 1–4)demonstrated a pattern with grade 2 as the most prevalent(43.6–46.0%) during treatment and in the early period from1–6 months after radiotherapy and grade 1 as the secondmost prevalent (24.3–37.5%) (Table 3). Hereafter, a shiftwas demonstrated, with grade 1 xerostomia as the mostprevalent (39.2–41.7%) in the late period 6 months to morethan 1 year post-treatment and grade 2 as the second mostprevalent (23.9–37.8%; Table 3). Grade 2 was at its lowestmore than 2 years after irradiation (Table 3). Grade 3xerostomia showed some fluctuation with 11.5% duringtreatment, 3.9% at the lowest 1–3 months after radiotherapyand 15.6% at the highest more than 2 years after treatment(Table 3). Grade 4 xerostomia was not introduced until lateafter radiation therapy and only affected a few percentagesof the cancer population treated by head and neckirradiation (Table 3).

The weighted and pooled whole saliva secretionsshowed profoundly lower unstimulated and stimulatedwhole salivary flow rates during radiation therapy with afurther reduction at 1–3 months post-treatment (Fig. 3).However, slightly higher unstimulated and stimulatedwhole saliva flow rates were shown from 1 year and6 months, respectively, and up to 2 years after radiotherapy(Fig. 1). The period from 1 year following radiotherapywith slightly higher salivary flow rates corresponds to theperiod with a shift toward higher prevalences of grade 1and lower grade 2 xerostomia (Table 3). In addition, thestimulated secretion was consistently higher than theunstimulated secretion, implying a residual capacity ofthe salivary gland tissue and a potential of stimulatorymanagement of xerostomia following head and neckirradiation (Fig. 3).

Conventional radiotherapy

Eighty-two studies assessed salivary gland function inrelation to conventional radiation therapy (studies includedaccelerated, hyperfractionated, and boost radiotherapy,concomitant chemotherapy, and chemotherapy boost).Fifty-nine were cohort studies, 22 were cross-sectionalstudies, one was a case–control study, and 24 studies werecontrolled. Twenty-six studies measured salivary glandhypofunction (25 salivary flow rate and one scintigraphy)and 66 studies assessed xerostomia (only ten studiescombined assessments of salivary gland hypofunction andxerostomia).

Xerostomia is the most frequent and permanent com-plaint after conventional radiotherapy [16–63] and is relatedto the cumulative dose of irradiation and the volume ofsalivary gland tissue that has been included in the treatmentportals [57, 64–68]. When all salivary glands are included(e.g., nasopharyngeal carcinoma), the highest prevalenceand severity of salivary gland hypofunction and xerostomiahas been reported, followed by radiation treatment oforopharyngeal carcinoma, while the least dryness com-plaints and loss of salivary gland function were reported forradiation treatment of laryngeal/epilaryngeal cancer [18, 20,25, 28, 50, 69–72].

For our estimates of prevalence, data on xerostomiainduced by conventional radiotherapy could be extractedfrom 38 studies, but there were not sufficient data to reportseparately on the grading of xerostomia or salivary flowrates in response to conventional radiation therapy. Theweighted prevalence of xerostomia showed some fluctua-tion with 81.4% during treatment, 70.9% at the lowest1–3 months after radiotherapy, and 90.9% at the highestmore than 2 years after treatment (Table 3 and Fig. 1).Thus, no improvement was shown when comparing theprevalence during treatment and more than 2 years post-treatment (Table 3 and Fig. 1).

The literature review showed that unstimulated andstimulated saliva secretion decreases dramatically afterconventional radiation therapy, with the major salivaryglands included within the radiation portal [40, 52, 73–78].The severity of this damage is dependent on the cumulativeradiation dose and the proportion of the major salivaryglands included within the treatment portal and is thus lesspronounced in unilaterally irradiated patients [66, 69, 79–85]. The early response to irradiation results in decreasedsalivary flow rates within the first week of treatment, and asecond phase of decrease in secretion may be noted aftercompletion of radiation therapy, with no significantrecovery after high-dose (∼60 Gy to the salivary glandtissue) radiotherapy [40, 66, 74, 79, 80, 83, 84, 86, 87].This was also seen in our estimates of whole saliva flowrates (Fig. 1). Unfortunately, few studies assessed the actual


flow rate. Only one study assessed the flow rate of thebuccal and labial minor salivary glands and found both tobe significantly decreased after conventional radiationtherapy (head and neck cancer diagnoses not specified)

compared to healthy controls [76]. Furthermore, only onestudy assessed sequelae of childhood irradiation. The studypopulation had been treated for head and neck rhabdomyo-sarcoma from 7.5 to 33 years previously and 12% (2/17) of

Table 3 Weighted prevalence of xerostomia and severity grade by post-treatment phase and type of radiation therapy

Type of cancer therapy Pre-tx During RT 1-3 monthspost-RT

3-6 monthspost-RT

6-12 monthspost-RT

1–2 yearspost-RT

>2 yearspost-RT

All studies

Prevalence 6.0% 93.0% 73.6% 79.0% 82.9% 77.6% 85.3%

Std. err. 0.03 0.05 0.07 0.05 0.05 0.06 0.04

95% CI 0–3.9 82.9–100 58.9–88.4 68.1–89.9 72.6–93.2 64.7–90.6 77.6–93.0

Grade 1

Prevalence 5.4% 37.5% 24.3% 31.4% 39.2% 44.1% 41.7%

Std. err. 0.04 0.05 0.04 0.08 0.06 0.10 0.09

95% CI 0–62.6 26.5–48.5 14.4–34.2 13.6–49.2 24.9–53.4 18.9–69.2 22.4–61.0

Grade 2

Prevalence 0% 43.7% 46.0% 43.6% 35.0% 37.8% 23.9%

Std. err. NA 0.07 0.09 0.09 0.03 0.14 0.06

95% CI NA 28.4–59.1 27.0–65.0 22.7–64.5 28.8–41.2 3.1–72.5 10.4–37.4

Grade 3

Prevalence 0% 11.5% 3.9% 7.2% 5.7% 6.1% 15.6%

Std. err. NA 0.07 0.02 0.03 0.03 0.03 0.05

95% CI NA 0–26.7 0–9.9 1.2–13.2 0–11.8 0.3–11.9 4.3–26.8

Grade 4

Prevalence 0% 0% 0% 0% 2.6% 0% 1.7%

Std. err. NA 0 0 0 0.03 0 0.03

95% CI NA 0–0 0–0 0–0 0–10.0 0–0 0–8.4

References, see conventional RT, 3Dconformal RT and IMRTConventional RT

Prevalence 10.4% 81.4% 70.9% 83.2% 71.5% 83.8% 90.9%

Std. err. 0.07 0.09 0.09 0.06 0.09 0.09 0.03

95% CI 0–4.2 57.5–100 50.2–91.7 67.6–98.9 47.3–95.6 63.9-100 83.4–98.4

References [16, 17, 19, 22, 23, 26, 28,29, 31, 32, 35, 37–39, 41, 44, 46–48,50, 53, 55, 58–60, 62–64, 67, 68, 71,89–91, 93, 104, 120, 199]3D conformal RT

Prevalence 0% NR 46.7% 74.5% 90.3% 75.4% 69.4%

Std. err. NA NA NA NA 0.05 NA

95% CI NA NA NA NA 10.1–100 NA

References [95, 99, 104, 105, 107]

IMRT

Prevalence 11.8% 100% 89.4% 72.7% 90.1% 66.0% 68.1%

Std. err. NA 0.04 0.10 0.10 0.04 0.11 0.06

95% CI NA 90–100 61.0–100 39.5–100 81.0–99.2 34.3–97.7 40.4–95.7

References [109, 118–122, 124, 126–129,131, 133, 136–139, 142, 144–146,149, 151–153]

Tx treatment, Std. err. standard error, CI confidence interval, NR none reported, NA not applicable, since data derived from one study only, RTradiation therapy, 3D three-dimensional, IMRT intensity-modulated RT


survivors reported suffering from xerostomia [88]. Thislower prevalence of xerostomia in the latter patient groupcompared to patients treated for head and neck cancer isalso due to the lower cumulative radiation dose applied inthe treatment of rhabdomyosarcoma.

Concomitant chemotherapy usually had been adminis-tered in a proportion of the radiation patients included inthe various studies, and data on salivary flow rate andxerostomia were generally not reported separately for thispatient group. Thus, no firm conclusion can be drawn ifconcomitant chemotherapy and radiation therapy has apotential additive effect on salivary gland hypofunction [24,36, 48, 67, 72, 89–94].

3D conformal radiotherapy

Fourteen studies assessed 3D conformal radiotherapy andeffects on salivary gland function: 13 cohort studies andone cross-sectional study. Three studies were controlled.Eight studies reported data on salivary gland hypofunction(seven salivary flow rates and one scintigraphy), and 11studies assessed xerostomia. The studies demonstratedconsensus that reduced radiotherapy dosages by 3Dconformal radiotherapy to contralateral parotid glandsresulted in less loss of salivary gland function post-radiotherapy up to 2 years after completion of radiotherapy[95–102] and 3D conformal radiotherapy to have a

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Salivary flow rate during and after chemotherapy

Unstim. whole saliva

Stim. whole saliva

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Fig. 4 Pooled and weighted data of unstimulated and stimulatedwhole saliva flow changes with chemotherapy. Tx treatment, CTchemotherapy, Mo. months, Unstim. unstimulated, Stim. stimulated.Based on references [27, 179–184, 186, 188, 190, 192]

0102030405060708090

100

During RT 1-3 mo. post-RT

3-6 mo. post-RT

6-12 mo. post-RT

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>2 yrs. post-RT

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Xerostomia during and after radiotherapy

VAS score

Fig. 2 Pooled and weighted data of xerostomia assessed by visualanalog scale (VAS) during and after head and neck radiotherapy. RTradiotherapy, Mo. months, Yrs. years. Based on references [20, 25, 27,33, 37, 42–45, 49, 51, 52, 54, 55, 58, 61, 67, 70, 72, 92, 100, 108,110, 113, 116, 122, 130, 132]

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Pre-tx During RT

1-3 mo. post-RT

3-6 mo. post-RT

6-12 mo. post-RT

1-2 yrs. post-RT

>2 yrs. post-RT

ml/m

in

Treatment phase

Salivary flow rate during and after radiotherapy

Unstim. whole saliva

Stim. whole saliva

1.4

1.2

1.0

0.8

0.6

0.4

0.2

Fig. 3 Pooled and weighted data of unstimulated and stimulatedwhole saliva flow changes during and after head and neck radiother-apy. Tx treatment, RT radiotherapy, Mo. months, Yrs. years, Unstim.unstimulated, Stim. stimulated. Based on references [27, 31, 40, 54,64, 66, 67, 69, 73, 74, 76–80, 83, 84, 86, 97, 102, 110, 115, 118, 122]

0102030405060708090

100

Pre-tx During RT

1-3 mo. post-RT

3-6 mo. post-RT

6-12 mo. post-RT

1-2 yrs. post-RT

>2 yrs. post-RT

Pre

vale

nce

Treatment phase

Xerostomia during and after radiotherapy

All RT therapies Conv. RT

3D-CRT IMRT

Fig. 1 Pooled and weighted prevalences of xerostomia induced byhead and neck radiotherapy. RT radiotherapy, Conv. conventional, 3D-CRT 3-dimensional conformal RT, IMRT intensity-modulated RT, Txtreatment, Mo. months, Yrs. years. Based on references in Table 3


potential to decrease the prevalence and severity ofxerostomia [95, 99, 100, 103–107]. As was shown forconventional radiotherapy, xerostomia was also shown tobe significantly worse following bilateral 3D conformalradiotherapy compared to unilateral treatment [108].

For our estimates of prevalence, data on xerostomiainduced by 3D conformal radiotherapy could be extractedfrom five studies, but there were not sufficient data to reportseparately on the grading of xerostomia or salivary flowrates. The weighted prevalence of xerostomia is seen inTable 3 and Fig. 1. Since very few data were available,results are only reported for some assessment time points.The result at 1–3 months after irradiation showed a lowprevalence of xerostomia, but this was based on only onestudy of mixed cancer diagnoses not including nasopharyn-geal cancers (Table 3 and Fig. 1). At 6–12 months post-treatment, the xerostomia prevalence was at the same level asthe results of IMRT and higher than conventional radiother-apy, while more than 1 year post-treatment, the prevalencewas lower than after conventional radiotherapy andapproaching the same level as IMRT (Table 3 and Fig. 1).

Intensity-modulated radiation therapy

IMRT allows more accurate delivery of specific radiationdosage and dose distribution to the tumor mass according totumor location and severity, with sparing of the normaltissue and organs at risk, e.g., salivary glands. IMRT wasevaluated in 49 studies; two randomized controlled trials(both nasopharyngeal cancer), 38 cohort studies, two case–control and seven cross-sectional studies. Thirty-threestudies were not controlled. Eighteen studies reported dataon salivary gland hypofunction (13 salivary flow rate andfive scintigraphy), and 44 studies assessed xerostomia.Finally, only one study assessed IMRT and xerostomia in apediatric population [109].

Based on the two randomized controlled trials, IMRT ofearly stage nasopharyngeal carcinoma compared to con-ventional/2D radiotherapy resulted in sparing of salivarygland function one year after treatment [110, 111].Regarding xerostomia 1 year after treatment, one of therandomized controlled trials found lower prevalence ofphysician-assessed grades 2–4 oral dryness with IMRT, butno difference in patient-assessed oral dryness betweenpatients treated with IMRT or 2D radiotherapy [111], andthe other found no difference in physician-assessed oraldryness between IMRT and conventional radiotherapy, butthe symptom of sticky saliva to be significantly lower withIMRT than conventional radiotherapy [110].

In summary, from the various cohort, case–control andcross-sectional studies several consensus conclusions canbe drawn. Parotid-sparing IMRT have the potential todecrease the prevalence and severity of salivary gland

hypofunction [110–114], and the saliva secretion fromspared salivary glands may also have the potential ofincreasing over time after therapy, unlike when treated byhigh-dose conventional radiation therapy [110, 111, 113,115–123]. Furthermore, a large variety in mean cumulativeradiation doses to parotid gland tissue has been reportedabove, which radiation damage to parotid glands has becomeirreversible. These cumulative doses range from ≤26–30 Gy[112, 115, 117, 118, 123, 124] and <38 Gy [121] to <40 Gy[82]. The differences in the reported dose ranges may partlybe due to few cases with a low mean parotid dose, thusrendering dose–response curves with greater statisticaluncertainty [125].

For our estimates of prevalence, data on xerostomiainduced by IMRT could be extracted from 25 studies, butthere were not sufficient data to report separately on thegrading of xerostomia or salivary flow rates. The weightedprevalence of xerostomia is seen in Table 3 and Fig. 1. Theresults showed a 100% prevalence of xerostomia duringIMRT, which was higher than during conventional irradia-tion (Table 3 and Fig. 1). At 6–12 months post-treatment, thexerostomia prevalence was at the same level, as the results of3D conformal radiotherapy and higher than conventionalradiotherapy, while more than 1 year post-treatment, theprevalence was lower than after conventional radiotherapy(Table 3 and Fig. 1). The results at 6–12 months after IMRTshowed a peak in the prevalence of xerostomia; likewise, theresults 6–12 months after conventional radiotherapy showeda slope down (Fig. 1). Accordingly, when interpreting thedata, it has to be taken into consideration that different headand neck cancer diagnoses are pooled both within andbetween studies, and the distribution of nasopharyngealcancers and laryngeal cancers in the included studies maysignificantly impact the prevalence of xerostomia to a higheror lower level, respectively.

The literature review showed that parotid sparing IMRThave the potential of decreasing the prevalence and severityof xerostomia [103, 110–113, 120, 126–150]. After aninitial post-IMRT decline (1–3 months), salivary secretionand xerostomia gradually recover over time (1–2 years)[110–113, 115, 116, 118, 120–124, 126, 130, 134, 144,146, 149, 151–154]. Nevertheless, incomplete improvementin xerostomia by sparing of the parotid gland via IMRTemphasizes the need to enhance protection of the subman-dibular glands as the greatest contributors to whole salivaduring rest as well as the sublingual and minor salivaryglands. As such, submandibular/sublingual sparing IMRTcan be of relevance in selected patients [155] also becausethe seromucous submandibular saliva is a better moistenerfor the oral tissues than the pure serous parotid secretion.Comparable to data on parotid gland sparing, a mean doseof ≤39 Gy has been found for potential recovery ofsubmandibular/sublingual gland function over time [156].


In addition, sparing minor salivary glands might be veryuseful and applicable; as with IMRT, the mean radiationdose to the oral cavity can be reduced [113].

Radioactive iodine treatment

Ten studies assessed effects of radioactive iodine treatmentof thyroid cancer on salivary glands: eight cohort studiesand two cross-sectional studies of which three studies werecontrolled. Radioactive iodine is actively accumulated insalivary gland tissue, and sialadenitis is a common sequela[157–162] along with decreased salivary secretion andxerostomia [157–159, 161–163]. Salivary gland hypofunc-tion and xerostomia following radioactive iodine treatmenthas, by most authors, been reported to be dependent oncumulative activity [157, 158, 163], while others did notfind this coherence [161]. A low prevalence of xerostomia(5%) has been observed within a few days after low-doseradioactive iodine treatment [164], which is comparablewith the prevalence of xerostomia in the normal population[165], while higher prevalences have been found after high-dose iodine treatment.

For our prevalence calculations, data on xerostomiainduced by radioactive iodine treatment could be extractedfrom only six studies, and there was insufficient data availableto report on the grading of xerostomia or salivary flow rates.The weighted prevalence of xerostomia was 0.5% (0.01;0–7.7) (standard error; 95% confidence interval) beforetreatment [161, 162], and 33.6% (0.1; 0–75)–37.8% (0.07;15.8–59.8) at 1–2 years after treatment [158, 162, 163, 166].

The literature review showed that only four studiesreported data on salivary gland hypofunction. Assessmentwas done by scintigraphy in two studies [158, 163] and bysialometry in another two [166, 167]. The scintigraphystudies revealed a higher impairment in salivary glandfunction in parotid glands than in submandibular glands. Asialometry study showed unstimulated and stimulatedwhole saliva flow rates to be reduced by 27–41 and 27–36%, respectively, in a small cohort study of only fourpatients and a larger cross-sectional study within a timespan of 4 months to 20 years after radioactive iodinetreatment [167]. Another study assessing unstimulatedwhole saliva flow rate did not find any difference betweenpatients at 8.4±7 years after radioactive iodine treatmentcompared to thyroid cancer patients only treated surgically[166].

Conditioning total body irradiation/chemotherapyand hematopoietic stem cell transplantation

Eleven studies were included, examining effects of condi-tioning total body irradiation and/or chemotherapy andhematopoietic stem cell transplantation on salivary gland

function (the specific effects of graft versus host disease isnot included in the present systematic review, althoughsome patients in the included studies developed graft versushost disease at some time point of the study period). Thesaliva-related end point was salivary flow rate in ninestudies and xerostomia in three studies; three studies werecross-sectional (one study was controlled) and nine werecohort studies (three were controlled and one studyincluded both a cohort and cross-sectional design).

It was reported that patients may suffer from xerostomiaafter conditioning by total body irradiation prior to high-dosechemotherapy and bone marrow transplantation [168, 169].

For our prevalence calculations, very few numbers onthe prevalence of xerostomia induced by conditioning totalbody irradiation/chemotherapy and hematopoietic stem celltransplantation could be extracted from three studies. Therewere not sufficient data available to report on neither thegrading of xerostomia, salivary flow rates nor pretreatmentfor comparison. The weighted prevalence of xerostomiaduring treatment was 40.2% (0.15; 0–100) [168, 169], andone study reported 79% at 6.9 years after treatment [170].

The biological effects of radiation on salivary gland tissueare greatly dependent on how the physical dose is delivered. Ahigher radiation dose per fraction, as in total body irradiation,with a lower cumulative dose results in less salivary tissuedamage when compared to a radiation fractionation schemewith lower radiation dose per fraction but much highercumulative dose in head and neck cancer patients.

With regards to salivary flow rate, stimulated wholesaliva flow rate has been reported to be significantly morereduced within 3 months after bone marrow transplantationin children (before the age of 12 years) preconditioned bytotal body irradiation combined with chemotherapy com-pared to children preconditioned by chemotherapy only[171]. This is consistent with findings of other studies ofunstimulated and stimulated whole saliva and stimulatedparotid saliva in mixed pediatric/adolescent and adultpopulations [172–174]. However, one study examiningunstimulated whole saliva flow rate did not find adifference from before hematopoietic stem cell transplanta-tion compared to up to 3 months after treatment in a smalladult population when the conditioning regimen consistedof high-dose chemotherapy only [175].

After bone marrow transplantation (4–12 years aftertreatment), normal stimulated whole saliva secretion hasbeen reported in children conditioned with chemotherapy,while conditioning regimens including total body irradia-tion may result in a permanent reduction [171, 176].Normal unstimulated and stimulated whole salivary flowrates have also been reported in a small group of adultpatients a few years after total body irradiation, high-dosechemotherapy, and bone marrow transplantation [172]. Theprevalence of hyposalivation (unstimulated whole saliva)


has been reported to be about 26% of pediatric and adultstudy populations at cross-sectional examination at a meanof 1.5 and 6.9 years after bone marrow transplantation instudy populations with pooled conditioning regimens ofchemotherapy as well as chemotherapy/total body irradia-tion, and hyposalivation (stimulated whole saliva) wasreported to affect 31% and 61% of the patients in therespective studies [170, 177].

When looking separately at conditioning with chemo-therapy or total body irradiation, hyposalivation of stimu-lated whole saliva has been reported to be present in 26%and 54–70% of the pediatric patients, respectively [176,178]. Furthermore, stimulated whole salivary flow rate haseven been reported to exceed the baseline level 4 years afterbone marrow transplantation in children preconditionedwith chemotherapy while still decreased in total bodyirradiated patients [171].

Finally, it has been reported that significant risk factorsfor low stimulated whole saliva secretion in children afterbone marrow transplantation were conditioning with totalbody irradiation, recipient female sex, and seropositivity forat least three herpes viruses [178]. If none of the risk factorswas present, the estimated probability of stimulated wholesaliva hyposalivation was 1%, whereas the probability was68% when all risk factors were present [178].

Cancer chemotherapy

Sixteen studies were identified assessing salivary glandfunction in relation to cancer chemotherapy. The saliva-related end point was salivary flow rate in 11 studies,xerostomia in two studies, and another three studiesassessed both parameters. Ten of the studies were cohortsand six were cross-sectional of which six and four werecontrolled, respectively. The results show divergence likelydue to few and heterogeneous studies regarding underlyingcancer diagnoses, chemotherapy regimens, different studyperiods in relation to administration of chemotherapeutics,and number of previous chemotherapy cycles. Therefore, itis not possible to draw any consistent conclusion on theeffects of cancer chemotherapy on prevalence of salivarygland hypofunction and xerostomia.

Reports of salivary flow rate in adult acute leukemiapatients suggest that whole saliva flow rates decreaseswithin a few days following induction therapy and thenreturns toward baseline level within 1–2 weeks [179–182].Along this line, hyposalivation of stimulated whole saliva(i.e., <0.7 ml/min) was found in up to 75% of acuteleukemia patients during chemotherapy [179]. Furthermore,significantly decreased unstimulated and stimulated wholesaliva flow rates and significantly increased prevalence ofxerostomia also has been found during and 6months followingadjuvant moderate standard dose chemotherapy (cyclophos-

phamide, epirubicin/methotrexate, and 5-fluorouracil) for solidtumors (i.e., breast cancer) [183, 184]. Cross-sectionalexaminations during or 1/2–7 years after chemotherapy ofadult and childhood solid and hematological malignanciesalso suggested decreased saliva secretion and xerostomia[185–187]. On the contrary, other studies of moderate andintensive chemotherapy regimens in the treatment of hema-tological malignancies did not reveal changes in unstimulatedand stimulated whole saliva secretion during [27, 188, 189],within a few weeks after [190] or up to several years aftertreatment [191, 192]. Finally, it has been reported thatpatients having low salivary secretion before cancer treatmentseem to be at higher risk of developing hyposalivation inresponse to chemotherapy and to have prolonged recovery[184, 193].

For our prevalence calculations, data on xerostomiainduced by chemotherapy could be extracted from fourstudies, but there were not sufficient data to report on thegrading. The weighted prevalence of xerostomia showed aprevalence of 49.9% (0.04; 33.6–66.2) during chemotherapy[185, 187, 190], while a single study reported prevalencesbefore treatment of 7% and after treatment, i.e., 47% at6 months and 48% at 1 year after chemotherapy [184]. Theweighted unstimulated and stimulated whole salivary flowrates were based on data extracted from 11 studies [27,179–184, 186, 188, 190, 192], and the pooled flow ratesseemed mainly unchanged during chemotherapy. From 6 to12 months after chemotherapy, the stimulated wholesalivary flow rates tended to be higher than during and upto 6 months after chemotherapy (Fig. 4).

Thus, data suggest that some patients temporarilymay suffer from distinct hyposalivation and xerostomiaduring and following cancer chemotherapy, while othersare not affected to any noticeable extent. Unfortunately,most studies assessed salivary gland function onlyduring chemotherapy with no long-term follow-up.Furthermore, because the treatment regimens differdepending on cancer diagnoses and since differentantineoplastic medications are likely to have differentmechanisms of action on a cellular level, it is necessaryto distinguish between individual chemotherapy regi-mens in the study designs to arrive at any usefulconclusions regarding adverse drug effects on salivarygland function.

Immunotherapy

Three cohort studies reported on the effect of immunotherapyas a cancer treatment modality and its effects on salivary glandfunction; one study was controlled. The saliva-related endpoints were salivary flow rates, although dryness of the mouthwas also briefly addressed. Salivary gland tissue is thought to


be a target organ for IL-2-mediated immunological reactions,inducing lymphocytic infiltration and cytokine productionleading to salivary gland hypofunction. Thus, intravenous orsubcutaneous administration of IL-2 in patients with meta-static cancer and in patients treated with autologous bloodstem cell transplantation for hematological malignanciesresulted in xerostomia and salivary gland hypofunction; yet,salivary gland hypofunction returned to baseline within2 weeks after treatment, e.g., secretion of glandular salivawas decreased by 83–95 and 73–83% for unstimulated parotidand submandibular flow rates, respectively, and decreased by48–65 and 52–56%, respectively, during stimulated condi-tions [194–196]. IL-2-mediated salivary gland hypofunctionmay resemble graft versus host disease induced hyposali-vation, which may point to similar pathophysiologicmechanisms [195].

Salivary gland hypofunction and xerostomia-relatedQoL

Since the 1989 NIH Development Consensus Confer-ence, there has been increasing focus on the impact oforal complications of cancer therapies on QoL. QoL, asit applies to cancer patients, may be defined as apatient’s appraisal and satisfaction with their currentlevel of functioning compared to what is perceived to bepossible or ideal [197]. Thus, the impact of salivary glandhypofunction and xerostomia on QoL may be affected bypatient expectations, coping strategies, and changes in theway in which a patient evaluates overall well-being andsatisfaction over time. Accordingly, patients may haveaccepted that salivary gland hypofunction and xerostomiaare unavoidable after cancer treatment and therefore haveadjusted their expectations. Hence, this may partly explainif a lack of coherence is observed between QoL aspects,decreased salivary flow rates, and xerostomia followingcancer treatment.

The QoL instruments used in the studies included in thepresent review generally assessed symptoms or functionalproblems, such as ability to speak, chew, and swallow, towear dentures, oral comfort/pain, or sleep disturbance.QoL domains assessed by the instruments includedphysical function, role function, social function, emotionalfunction, cognitive function, and general health status anddid not include the direct impact of xerostomia andsalivary gland hypofunction. However, QoL may besignificantly influenced by xerostomia and salivary glandhypofunction in addition to the presence of other majororal complications of cancer therapy, such as mucositis,soft tissue destruction, surgical sequelae, oral mucosalinfection, pain, taste loss, trismus, or carious destructionof teeth [8, 9].

Accordingly, in our analysis of xerostomia-related QoL,studies were included if they specifically related salivarygland hypofunction or xerostomia to QoL domains. Thus,single-item questions of dry mouth symptoms, that is, thesubjective amount or consistency of saliva without corre-lation to QoL domains, was interpreted as a measure ofxerostomia and not included as xerostomia-related QoL.

Conventional radiotherapy and salivary glandhypofunction/xerostomia-related QoL

Ten studies correlated xerostomia to QoL aspects followingconventional radiotherapy. Studies have found that lowerunstimulated and stimulated whole saliva flow rates andxerostomia worsen overall QoL and domains of senses,speech, sleep, eating, swallowing, social contact/eating,dyspnea, need for nutritional support, and deterioratessubjective vocal function and speech performance in hetero-geneous head and neck cancers [58, 67, 198–200]. In linewith this, xerostomia has also been shown to negativelyaffect physical, role, emotional and social function, symp-toms of dyspnea, appetite loss, as well as overall QoL inlaryngeal/hypopharyngeal cancer patients [201], although thelatter patients are affected by xerostomia to a lesser degreethan diagnoses of nasopharyngeal, oropharyngeal, and oralcavity cancers [18, 20, 25, 28, 50, 69–72]. The impact ofxerostomia on general aspects of QoL following conven-tional radiotherapy has also been shown to be morepronounced in female and younger patients [53]. In patientswith a diagnosis of cancer of the base of the tongue, a highpercentage (89%) found that xerostomia caused moderate tosevere distress 5 years after radiotherapy [17]. On the otherhand, 1 year after chemoradiation in a cohort of heteroge-neous head and neck cancer patients, xerostomia appeared tohave little impact on performance, global QoL, or specificQoL aspects, although xerostomia was reported as asignificant problem by over three quarters of patients [18].Along this line, no significant relation was found betweenglobal QoL, stimulated parotid flow rate, and dry mouthsymptoms. Patients experience normalized overall QoL inspite of the presence of moderate to severe xerostomia yearsafter radiation therapy [52].

3D conformal radiotherapy and salivary glandhypofunction/xerostomia-related QoL

Four studies evaluated xerostomia-related QoL during andfollowing 3D conformal radiotherapy. Two studies ofinvasive cancer of the head and neck (diagnoses not furtherspecified) assessed xerostomia-related QoL by a validated15-question scale [98, 100], one study of oro- andnasopharyngeal cancers by a five questions xerostomia-related QoL questionnaire [103], and one study of mixed


cancer diagnoses of oral cavity, nasopharynx, oropharynx,hypopharynx, and larynx assessed xerostomia by theRTOG/EORTC Late Radiation Morbidity Scoring Systemand correlated it to health-related QoL evaluated by theEORTC QLQ-C30 [105]. These studies found thatxerostomia-related QoL had significantly worsened at thecompletion of the radiotherapy course compared to baselinebut improved 1 month after treatment [98]. Six months after3D conformal radiotherapy, xerostomia significantly hasaffected health-related QoL, although slight xerostomia didnot have a clinically relevant impact, whereas severexerostomia was shown to have a moderate impact onemotional function and fatigue and a large impact on socialfunctioning and global QoL [105]. In addition, xerostomia-related QoL responses were reported to be markedly betterat 1 year after radiotherapy than at the completion of theradiotherapy course but are still significantly worse thanbaseline [98, 100, 103]. Other authors reported the impactof xerostomia to be relatively low up to 18 months afterradiation therapy and then increasing at 24 months aftertreatment [105]. Finally, individuals with higher unstimu-lated and stimulated parotid flow rates at completion ofradiotherapy and up to 1 year after radiotherapy wereshown to report better QoL scores than those with lowersalivary secretion [98].

IMRT and salivary gland hypofunction/xerostomia-relatedQoL

Eleven studies specifically assessed the impact of xerosto-mia or salivary gland hypofunction on QoL aspects inrelation to IMRT (Table 4) [103, 110, 112, 113, 116, 117,130, 132, 140, 150, 202]. The results reported in this tablesuggest that decreasing xerostomia by partly sparing ofparotid gland function by IMRT has the potential ofimproving some QoL domains compared to conventionalor 3D conformal radiotherapy [103, 110, 112, 117, 130,132, 140, 150]. The variation of results also clearlyillustrates the diversity of assessment scales used and thechallenge of drawing general conclusions (Table 4).

To summarize, after parotid sparing IMRT, an associa-tion was found between xerostomia and QoL (Table 4),with a decline in QoL in the 6-month period after RT andthen followed by improvement of xerostomia-related QoLup to 24 months after radiation therapy [103, 113, 116, 130,132, 140]. Thus, the potential benefits from IMRT onxerostomia-related QoL are most pronounced late(≥6 months) after therapy (Table 4).

Regarding the impact of salivary gland hypofunction onQoL (Table 4), whole saliva flow rates, both unstimulatedand stimulated, were related to oral comfort, speech,chewing/swallowing, and sleep [112], to a combined QoLscore of xerostomia’s impact on daily activities, sleeping

patterns, speech, and swallowing [117], and to emotionalfunction [110]. On the other hand, unstimulated andstimulated whole saliva flow rate did not correlate toMedical Outcome Short Form 36 QoL scores [110, 202]. Inaddition, unstimulated and stimulated parotid and subman-dibular flow rates could not be shown to be associated withQoL scores up to 2 years after radiotherapy [113, 116],except for one report showing a correlation betweenstimulated parotid flow rate and speech problems [110].

Other cancer therapies and salivary glandhypofunction/xerostomia-related QoL

No studies assessed QoL in relation to salivary glandhypofunction or xerostomia as sequelae of cancerchemotherapy, conditioning total body irradiation/chemo-therapy and hematopoietic stem cell transplantation,radioactive iodine treatment, and cancer therapies inchildren/adolescents.

Epilogue

Salivary gland hypofunction and xerostomia are frequentlyreported and clinically significant adverse effects of cancertherapies. Differences in tumor site, stage, and treatmentregimens produce different severities of salivary glandhypofunction, xerostomia, and impact on QoL aspects.This is mainly related to the involvement of the majorsalivary glands in the radiation treatment portals, asradiotherapy is shown to be the major cause of salivarygland hypofunction and xerostomia in head and neckcancer patients. Within the radiation techniques that arecurrently routinely applied in the clinic, IMRT has thegreatest potential of sparing salivary gland tissue resultingin a better preservation of salivary gland function in headand neck cancer patients. The future focus should be onoptimized or new approaches to further reduce thecumulative radiation dose to the parotids and likely to thesubmandibular/sublingual and minor salivary glands withregards to reducing xerostomia and the potentially severeconsequences of decreased saliva secretion on health.Particularly, a shift of the focus of preserving the parotidglands toward preserving the submandibular and minorsalivary glands is of utmost importance, as the non-serousglands are the major contributors to the continuousmoistening of the oral tissues. Probably, when the functionof the latter glands can be better preserved, a bettercorrelation between the level of salivary secretion remainingafter cancer treatment and xerostomia-related QoL aspectscan be perceived.

As was shown, the heterogeneity of diagnoses andtreatment parameters within studies has resulted in difficul-


Tab

le4

Studies

assessingqu

ality

oflife(Q

oL)aspectsrelatedto

saliv

aryglandhy

pofunctio

nand/or

xerostom

iaafterintensity

-mod

ulated

radiationtherapy(IMRT)forhead

andneck

cancer

Autho

rsCancersite

Treatmentmod

ality

(n)

QoL

questio

nnaire

Salivarygland

secretion/

xerostom

ia

Tim

eof

assessment

Correlatio

nof

saliv

aryglandfunctio

nandQoL

Chaoet

al.[112]

Mixed

H&N

IMRT(27)

XQoL

QUWSandSWS

6monthsafterRT

UWSandSWScorrelated

positiv

elyto

scores

ofxerostom

ia,

oral

comfort,speech,chew

ing/sw

allowingandsleep(higher

scores

indicatin

gless

difficulty

with

oral

dryness)

3D-RT(14)

Eisbruchet

al.[113]

Mixed

H&N

IMRT,

unilateral(48)

andbilateral(84)

UM-X

QUPS,SPS,USS

andSSS

1,3,

6,12

,18

and

24mon

thsafterRT

The

UM-X

Qsummaryscores

increasedby

1mon

thafterRT

Xerostomia

UM-X

Qsummaryscores

decreasedby

18and24

mon

ths

Little

effect

ofRTon

xerostom

ia-related

sleeping

problems

Salivaryflow

ratesno

tassociated

with

UM-X

Qscores

Lin

etal.[116

]Mixed

H&N

IMRT(36)

HN-Q

oLUPS,SPS,USS

andSSS

3,6and12

mon

ths

afterRT

Xerostomiacorrelated

toeatin

g,communication,

emotionand

pain

domains

UM-X

QXerostomia

Xerostomia

andQoL

scores

improved

from

3-12

months

afterRT

Salivaryflow

ratesno

tassociated

with

QoL

scores

Blancoet

al.[117]

Mixed

H&N

IMRT(45)

XQoL

QUWSandSWS

6and12

mon

ths

afterRT

SWSim

proved

from

6to

12monthsafterRTandcorrelated

positiv

elyto

QoL

scores

(higherscores

indicatin

gbetterQoL

)3D

-RT(14)

and3D

-RT

+IM

RTbo

ost(6)

Jabbariet

al.[130]

Mixed

H&N

IMRT(30)

HN-Q

oLXerostomia

1,3,

6,12

,18

and

24mon

thsafterRT

Xerostomia-related

QoL

declined

intheperiod

of6

months

afterRTin

both

groups.T

hereafterim

prov

ementafterIM

RT

butno

tafterconv.RT

Conv.

RT(10)

UM-X

Q

Nget

al.[103]

Mixed

H&N

IMRT(38)

XQoL

QXerostomia

IMRT14

(6–31)

mon

thsafterRT

IMRThadlower

scores

comparedto

conv.RTin

overall

XQoL

Qscoreandregardingindividual

questio

nsof

xerostom

iaandim

pact

ofdrymou

thon

speech,

chew

ing/sw

allowingandsleep

Conv.

RT(44)

Conv.

RT20

(6–34)

mon

thsafterRT

Pacholkeetal.[13

2]Mixed

H&N

IMRT(27)

UM-X

QXerostomia

>12

mon

thsafterRT

Low

UM-X

Qscores

inlaryng

ealgrou

pandhigh

inconv.

bilateralRT(total

irradiationof

major

saliv

aryglands)

comparedto

IMRT,

conv.ipsilateralandbilateral(partly

irradiationof

parotid

glands)RT

4grou

psof

conv.RT

Differences

betweentheconv.ipsilateral,bilateral(partial

irradiationof

parotid

glands)andIM

RTgroups

werenot

statistically

significant

Larynxon

ly(35)

Ipsilateral(32)

Bilateralpartly

(11)

Bilateraltotal(105

)


Pow

etal.[110]

Early

stage

nasoph

aryn

geal

IMRT(24)

SF-36

SWSandSPS

2,6and12

mon

ths

afterRT

Nocorrelations

betweenSF-36subscale

scores

andsaliv

ary

flow

rates

Conv.

RT(21)

EORTCQLQ-C30

Xerostomia

SWScorrelated

negativ

elywith

EORTCQLQ-C30

global

health

(quotesthatitmight

bedueto

statisticalchance?)

and

positiv

elywith

emotionalfunctio

n.SPScorrelated

positiv

ely

with

role

functio

n

EORTCQLQ-

H&N35

SPScorrelated

negativ

elywith

EORTCQLQ-H

&N35

dry

mou

th,sticky

saliv

aandspeech

problems

IMRTbetterthan

conv.RTin

term

sof

improv

edQoL

Dalyet

al.[140]

Mixed

H&N

IMRT(29)

UM-X

QXerostomia

IMRT18

(6–56)

mon

thsafterRT

IMRThadlower

scores

comparedto

conv.RTin

overall

UM-X

Qscores

andregardingindividual

questio

nsof

xerostom

ia-related

talkingandchew

ingdifficulty,

xerostom

iawith

orwith

outeatin

g,andfrequencyof

sipp

ing

liquidwith

andwith

outeatin

g

Conv.

RT(75)

Conv.

RT42

(7–148

)mon

thsafterRT

Lin

etal.[202]

Mixed

H&N

PooledIM

RT(32)

and3D

-RT(18)

SF-36,

Taiwanese

UWS

Before,

and2,

4,6

and8

weeks

after

startin

gRT

UWScorrelated

negativ

elyto

UM-X

Qscores

atalltim

epo

intsafterstartin

gRT,

butdidno

tcorrelateto

SF-36

QoL

scores

UM-X

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Xerostomia

UM-X

Qscores

correlated

negativ

elyto

SF-36scores

before,

4and6

weeks

afterstartin

gRT

Van

Rijet

al.[150

]Mixed

H&N

IMRT(75)

Study-specific

Xerostomia

IMRT2.3

yearsafterRT

IMRThadless

difficulty

swallowingfood

,needed

less

water

foradrymou

thdu

ring

day,

nigh

tandmeals,hadfewer

problemswith

speech

andeatin

gin

public

comparedto

conv.RT

Conv.

RT(87)

Conv.RT2.9

yearsafterRT

Laryngeal

cancer

patientshadfewer

complaints

than

oropharyngealcancer

patients

RTradiationtherapy,3D

three-dimension

al,H

&Nhead

andneck,C

onv.conv

entio

nal,UWSun

stim

ulated

who

lesaliv

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rate,S

WSstim

ulated

who

lesaliv

aflow

rate,U

PSun

stim

ulated

parotid

flow

rate,SP

Sstim

ulated

parotid

flow

rate,USS

unstim

ulated

subm

andibu

larflow

rate,SS

Sstim

ulated

subm

andibu

larflow

rate

Xerostomia-related

QoL

Questionn

aire

(XQoL

Q):five

questio

nsaddressing

xerostom

iaandim

pactof

drymou

thon

oralcomfort,speech,

chew

ing/sw

allowingandsleep(a

sixthqu

estio

ninclud

eswearing

dentures),VAS,high

erscoreindicatin

gbetterxerostom

ia-related

QoL

assessment.H&N

cancer-related

QoL

Questionn

aire

(HN-Q

oL):20

questio

ns,four

domains

addressing

eatin

g,commun

ication,

emotionandpain,0

–100

,higherscores

indicatin

gworse

QoL

assessment.University

ofMichiganXerostomiaQuestionn

aire

(UM-X

Q):eigh

tquestions

addressing

xerostom

iaand

impactof

drymou

thon

oralcomfort,speech,

eatin

g/chew

ing/sw

allowingandsleep,

11-point

ordinalLikertscalefrom

0to

10,finalsummaryscore0–

100,

high

erscores

indicatin

gworse

levelof

xerostom

iaor

discom

fortdu

eto

xerostom

ia.Xerostomia-related

QoL

Scale

(XQoL

S):15

questio

ns,four

domains

addressing

impact

ofsaliv

arydy

sfunctionandxerostom

iaon

pain/discomfort,

physical,p

ersonal/p

sycholog

icalandsocialfunctio

ning

,5-point

scale,percentage

ofmaxim

umscore,high

erscores

indicatin

gworse

QoL

assessment.MedicalOutcomeSho

rtForm

36(SF-36):3

6qu

estio

ns,eigh

tsubscales;ph

ysical,social,role

limitatio

n-ph

ysical,role

limitatio

n-em

otional,mentalhealth,vitality,pain

andgeneralhealth

perceptio

n,finalsummaryscore0–10

0,high

erscore

indicatin

gbetterhealth

status.Europ

eanOrganizationforResearchandTreatmentof

CancerCoreQuestionn

aire

[EORTC

QLQ-C30

(+3)]:33

questio

ns,five

functio

nalscales:ph

ysical,role,

emotional,cogn

itive

andsocial

functio

ning

;threesymptom

scales:fatig

ue,pain,nausea/vom

iting

;aglob

alQoL

scale;

andsixsing

leitemsconcerning

dyspnea,

sleepdisturbances

andfinancial

impact.Final

summaryscore1–10

0,high

erscorein

functio

nalscales

andglob

alQoL

indicatin

ghigh

/health

ylevelof

functio

ning

,high

erscorein

symptom

scales/item

sindicatin

ghigh

levelof

symptom

s/prob

lems.Europ

eanOrganizationforResearchandTreatmentof

CancerHeadandNeckCancerMod

ule(EORTCQLQ-H

&N35

):35

questio

ns,seven

multi-item

scales

assessingpain,

swallowing,

senses,speech,social

eatin

g,social

contact,andsexu

ality

;11

sing

leitemsabou

tteeth,

mou

thop

ening,

drymou

th,sticky

saliv

a,andcoug

hing

.Final

summaryscore1–10

0,high

erscorein

functio

nalscales

andglob

alQoL

indicatin

ghigh

/health

ylevelof

functio

ning

,high

erscorein

symptom

scales/item

sindicatin

ghigh

levelof

symptom

s/prob

lems


ties in interpretation of the outcomes, and genuine differ-ences in effects may be obscured. Hence, site- andtreatment-specific assessments could provide more preciseknowledge of the impact of cancer treatment on salivarygland hypofunction and xerostomia. However, this ap-proach would obviously increase the problem of smallstudy sample sizes, meanwhile emphasizing the need forlarge, multi-institutional, randomized studies to assesscancer treatments. However, when performing such trials,these trials would greatly benefit from universal applicationof standardized saliva collection procedures, a validatedxerostomia assessment scale (patient-assessed), and avalidated questionnaire specifically addressing the impactof xerostomia on QoL aspects [54, 135, 203].

Fields with sparsely available literature as identified bythis systematic review are salivary gland hypofunction andxerostomia in pediatric/adolescent cancer populations, sali-vary gland hypofunction/xerostomia as an oral complicationof cancer chemotherapy, radioactive iodine treatment, andtotal body irradiation/hematopoietic stem cell transplanta-tion. In addition, no firm conclusions could be drawn aboutthe potential additive effect of concomitant chemotherapyand radiotherapy on salivary gland hypofunction.

The abovementioned recommendations would be bene-ficial to be implemented in future studies both duringcancer treatment and in a life-long perspective.

Acknowledgements We thank Research Librarian Susie Andersen,Deputy Head of the Panum Library, Faculty of Health Sciences,University of Copenhagen, Denmark, for expert assistance with thesystematic literature search. We also thank Tainika Williams,Department of Oral Medicine, Carolinas Medical Center, NorthCarolina, USA, for her overall skills with literature search.

Conflicts of interest The authors declared that they have nopotential conflicts of interests.

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a systematic review of salivary gland hypofunction and xerostomia … · 2015-08-07 · therapy...

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